One-Step Synthesis of Functionalized Organoborates via Accelerated Direct Metal Insertion in the Presence of B(OBu) 3

Organometallic reagents are of increasing importance in organic chemistry, especially as key intermediates for the synthesis of biologically active compounds as well as natural products.¹⁹³ In particular, transition metal catalyzed cross-couplings using organometallic intermediates have become widely used synthetic tools. ^194,195 Negishi-,¹⁹⁶ Stille-,¹⁹⁷ Heck-,¹⁹⁸ and Suzuki-Miyaura-types^199,194b of reaction allow the concise construction of polyfunctional aromatics and heteroaromatics. The latter has especially proven to be outstandingly practical and has been extensively used in straightforward C-C bond formations.^200,201 Moreover, the applied organoboron compounds, such as boronic acids, boronic esters as well as organotrifluoroborates generally display great tolerance toward functional groups and possess reasonable thermal stability.²⁰⁰ However, the known methods for preparation of these reagents suffer from major drawbacks,²⁰⁰ such as multi-step syntheses, low atom-economy, expensive transition-metal catalysis or low tolerance towards functional groups.^202,203 Sparked by

193 a) I. Omae, in Applications of Organometallic Compounds, John Wiley and Sons: Chichester, 1998; b) P.

Knochel, in Handbook of Functionalized Organometallics, Wiley-VCH: Weinheim, 2005.

194 For reviews on Miyaura-Suzuki cross-coupling reactions, see: a) S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633; b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; c) G. A. Molander, B.

Canturk, Angew. Chem. Int. Ed. 2009, 48, 9240; d) A. Suzuki, Heterocycles 2010, 80, 15; e) S. R. Chemler, D.

Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544.

195 a) K. L. Billingsley, S. L. Buchwald, Angew. Chem., Int. Ed. 2008, 47, 4695; b) G. A. Molander, B. Biolatto, J. Org. Chem. 2003, 68, 4302; c) J. Monot,M. Makhlouf Brahmi, S.-H. Ueng,C. Robert, M. Desage-El Murr, D.

P. Curran, M. Malacria, L. Fensterbank, E. Lacôte, Org. Lett. 2009, 11, 4914; d) E. P. Gillis, M. D. Burke, J.

Am. Chem. Soc. 2007, 129, 6716; e) D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2009, 131, 6961;

f) Y. Yamamoto, M. Takizawa, X.-Q. Yu, N. Miyaura, Angew. Chem. Int. Ed. 2008, 47, 928; g) S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew. Chem. Int. Ed. 2008, 47, 1473; h) Z. Lu, G. Fu, Angew.

Chem. Int. Ed. 2010, 49, 6676; i) M. Butters, J. N. Harves, J. Jover, A. J. J. Lennox, G. C. Lloyd-Jones, P. M.

Murray, Angew. Chem. Int. Ed. 2010, 49, 5156; j) C. S. Cho, Cat. Commun. 2008, 9, 2261.

196 E.-I. Negishi, F. Liu, in Metal-Catalyzed Cross-Coupling Reactions, (F. Diederich, P. J. Stang, eds.), Wiley–

VCH, Weinheim, Germany, 1998, pp 1.

197 a) J. K. Stille, Angew. Chem. Int. Ed. 1986, 25, 508; b) T. N. Mitchell, Synthesis 1992, 803.

198 F. Diederich, P. J. Stang, in Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, Weinheim, 1998.

199 A. Suzuki, J. Organomet. Chem. 1999, 576, 147.

200 Reviews on the preparation of organoboron compounds, see: a) A. Pelter, K. Smith, H. C. Brown, in Borane Reagents, Academic Press: London, 1988; b) D. S. Matteson, in Reactivity and Structure Concept in Organic Synthesis: Stereodirected Synthesis with Organoboranes, Springer: New York, 1994; Vol. 32; c) M. Vaultier, B.

Carboni, in Comprehensive Organometallic Chemistry, G. Wilkinson, F. G. Stone, E. W. Abel, Eds., Pergamon:

New York, 1995; Vol. 11, p 191; d) K. Smith, A. Pelter, in Comprehensive Organic Synthesis, B. M. Trost, I.

Fleming Eds., Pergamon: New York, 1991; Vol. 8, p 703; e) M. Zaidlewicz, M. Krzeminski, Science of Synthesis, 2004, 6, 1097; f) M. M. Midland, Chem. Rev. 1989, 89, 1553; g) C. Ollivier, P. Renaud, Chem. Rev.

2001, 101, 3415; h) V. Darmency, P. Renaud, Top. Curr. Chem. 2006, 263, 71.

201 For reviews on organotrifluoroborates, see: a) A. Darses, J.-P. Genet, Chem. Rev. 2008, 108, 288; b) G.

Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275.

202 K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169.

203 P. Merino, T. Tejero, Angew. Chem. Int. Ed. 2010, 49, 7164.

Brown’s report,²⁰⁴ we envisioned a direct, facile, atom-economic and inexpensive route to polyfunctional and heterocyclic organoborates via direct metal insertion compensating the drawbacks mentioned above. In contrast to Brown’s method,²⁰⁴ we investigated a milder and more convenient method for the preparation of organoborates via direct magnesium insertion and in situ trapping with trialkylborates of type 78 displaying low Lewis acidity. Based on a recent publication by Knochel et al., we also utilized the accelerating effect of LiCl-additive in direct metal insertions allowing the presence of a broad range of sensitive functional groups in the organometallic reagent.205,206,207 Initially, we explored various borate sources for the in situ trapping of the generated organomagnesium intermediate. Thus, the reaction of an aryl bromide such as 4-bromoxylene (79a) with magnesium turnings (1.6 equiv) in the presence of LiCl (1.1 equiv) and a borate of type 78 (0.33 equiv) produces (25 °C, 20 min) tentatively the intermediate arylmagnesium bromide 80. This intermediate is immediately trapped by 78 generating an aryl borate of type 81 (Scheme 43).

Scheme 43. Preparation of aryl borate of type 81 via direct magnesium insertion in the presence of a boron source and LiCl.

Remarkably, the comparison of the conversion of the aryl bromide to the magnesium reagent in the presence and the absence of boron source clearly indicates slower rate of reaction in the latter case (Table 8, entry 1). Interestingly, various boron compounds of type 78, such as B(OMe)3 (78a), B(OEt)3 (78b), B(OiPr)3 (78c), B(OBu)3 (78d), B(OAc)3 (78e), and even NaB(OMe)4 (78f) or LiB(OMe)4 (78g), are feasible for in situ trapping of the magnesium reagent forming the trisarylborate 2b (Table 8, entries 28). However, the highest rates of reaction were observed with B(OBu)3. In conclusion, the insertion was accelerated, not only by the presence of LiCl, but also by the borate additive. For a general applicability, a fast substitution on the boron center, along with non-activating properties of sensitive functional groups induced by high Lewis acidity, is essential to avoid the formation of side products.

204 a) H. C. Brown, U. S. Racherla, Organometallics 1986, 5, 391-393; b) H. C. Brown, U. S. Racherla, J. Org.

Chem. 1986, 51, 427.

205 a) A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 6040; b) N.

Boudet, S. Sase, P. Sinha, C.-Y. Liu, A. Krasovskiy, P. Knochel, J. Am. Chem. Soc. 2007, 129, 12358; c) A.

Metzger, M. A. Schade, P. Knochel, Org. Lett. 2008, 10, 1107.

206 a) Y.-H. Chen, P. Knochel, Angew. Chem. Int. Ed. 2008, 47, 7648; b) Y.-H. Chen, M. Sun, P. Knochel, Angew. Chem. Int. Ed. 2009, 48, 7648.

207 a) F. M. Piller, P. Appukkuttan, A. Gavryushin, M. Helm, P. Knochel, Angew. Chem. Int. Ed. 2008, 47, 6802;

b) F. M. Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryushin, P. Knochel, Chem. Eur. J. 2009, 15, 7192.

Table 8. Preparation of organoborates of type 2b using various borate sources after 20 min at 25 °C.

entry borate yield^a of Ar₃BOR·MgBr

yield^a of Ar-MgBr^a

1 - - 54%

2 B(OMe)3 33% 60%

3 B(OEt)₃ 49% 39%

4 B(OiPr)3 51% 41%

5 B(OBu)₃ 64% 20%

6 B(OAc)3 43% 27%

7 NaB(OMe)₄ 28% 34%

8 LiB(OMe)4 41% 42%

[a] Determined by GC-analysis of an iodolyzed reaction aliquot.

Furthermore, an optimum ratio of B(OBu)3 to aryl bromide of 2:1 (ArBr:B(OBu)3) was found that allows sufficiently fast reaction times, while using only minimal amount of B(OBu)3. Thus, 4-bromoxylene (79a) reacted with Mg (1.6 equiv; 25 °C, 20 min) in the presence of LiCl (1.1 equiv) and B(OBu)3 (0.5 equiv) producing the aryl borate 82a in 83% yield (Scheme 44).

Scheme 44. Preparation of the aryl borate 82a using 0.5 equivalent of B(OBu)3.

Besides elemental magnesium, other metal sources are also feasible for the preparation of arylborates of type 83 using unactivated aryl bromides. Thus, oxidizable metals, such as Li, Na, or K, readily react with 4-bromoxylene (79a; 25 °C, 0.5–12 h) in the presence of LiCl (1.1 equiv) and B(OBu)3 (0.5 equiv) generating the expected aryl borates 83ac in more than 90% yield (Scheme 45). Interestingly, using the same conditions with 4-bromoxylene (79a;

25 °C, 2 h), calcium turnings also furnished the desired organoborate 83b (Scheme 45). Due to a thick impenetrable oxide surface, calcium turnings generally are inert in direct metal insertion reactions with aryl halides.²⁰⁸ Remarkably, due to the accelerating effect of B(OBu)3, activated aryl bromides such as 1-bromo-bis(trifluoromethyl)-benzene (79b) also react with rather unreactive, but inexpensive, metal sources, such as Al or Zn, leading to the corresponding arylborates 83ef (Scheme 45).

208 S. Krieck, H. Görls, L. Yu, M. Reiher, M. Westerhausen, J. Am. Chem. Soc. 2009, 131, 2977.

Scheme 45. Preparation of organoborates of type 5 using various metal sources.

In contrast to Negishi-¹⁹⁶ and Kumada-Corriu-type²⁰⁹ cross-couplings, the organometallic boron intermediates are readily isolated as well as stored displaying thermal stability also in protic or aqueous media. Hence, we investigated its use and reactivity especially in Suzuki-type cross-coupling reactions. We could show that a broad range of polyfunctional aromatics and heteroaromatics bearing sensitive or relatively acidic functional groups could be prepared without protective groups. Thus, the functionalized aryl bromides 79ae were readily reacted with Mg-turnings (1.6 equiv) in the presence of B(OBu)3 (0.5 equiv) and LiCl (1.1 equiv) providing the corresponding arylborates 84bg in ca. 90% yield (Scheme 46). Subsequent Suzuki-type cross-couplings with aryl halides, like chlorides, bromides and iodides, furnished the polyfunctional aromatics 86al in 7996% yield (Scheme 46).

Scheme 46. Preparation of organoborates of type 84 followed by Suzuki-type cross-coupling reactions with aryl halides (FG = functional group).

In particular, 1-bromo-bis(trifluoromethyl)-benzene (79b) was efficiently converted into the diarylborate 84b via the direct magnesium insertion (Mg (1.6 equiv), LiCl (1.1 equiv)) in the presence of trisbutylborate (B(OBu)3 (0.5 equiv), 25 °C, 15 min). Subsequent Suzuki cross-coupling^201b with the aryl bromides or iodides 85ac furnished the substituted biphenyls 86ac in 7991% yield (Table 9, entries 13). Additionally, a Suzuki-type cross-coupling of

209 a) R. J. P. Corriu, J. P. Masse, J. Chem. Soc. Chem. Commun. 1972, 144; b) K. Tamao, K. Sumitani, M.

Kumada, J. Am. Chem. Soc. 1972, 94, 4374.

84b with 5-bromovanillin (85d) bearing an aldehyde- and a hydroxy-function produced successfully the substituted vanillin 86d in 83% yield (Table 9, entry 4). Furthermore, using the same conditions, the dianisylborate 84c prepared from 4-bromoanisole (79c) readily furnished after the Pd-catalyzed cross-coupling the amino-, amido-, or ester-substituted biphenyls 86eg in 7996% yield (Table 9, entries 57). Similarly, direct insertion of alpha-bromostyrene (79d; 0 °C, 30 min) using Mg turnings (1.6 equiv) in the presence of LiCl (1.1 equiv) and B(OBu)3 (0.5 equiv) efficiently generated the distyrylborate 84d leading after Suzuki cross-coupling with ethyl 4-bromobenzoate (85g) to the ester-substituted 1,2-diphenylethylene 86h in 95% yield (Table 9, entry 8). Additionally, functionalized diarylborates such as 84e and 84f prepared from the corresponding aryl bromides 79e and 79f furnished after Pd-catalyzed cross-coupling with 85h or 85i functionalized biphenyls 86i or 86j in 8283% yield (Table 9, entries 9 and 10). Similarly, the diarylborate 84g afforded after Suzuki cross-coupling reactions with 5-bromoindole (85j) or 5-bromovanillin (85d) the substituted indole 86k in 92% yield or the polyfunctional vanillin derivative 86l in 87% yield (Table 9, entries 11 and 12).

Table 9. Preparation of functionalized aromatics of type 86 via direct magnesium insertion in the presence of LiCl and B(OBu)3 with aryl bromides of type 79 followed by Suzuki-type cross-coupling.

Entry Ar2B(OBu)2MgBr (conditions [T, t])

Electrophile Product, Yield^a

1

F₃C CF₃ B(OBu)₂MgBr

2

84b (25 °C, 15 min)

I

CO2Et

85a

F₃C

CF₃

CO₂Et

86a: 91%^b

2 84b

NH₂ CN

I

85b

F₃C

CF₃ CN

NH₂

86b: 87%^b

3 84b

OPiv

Br

85c

F₃C

CF3 OPiv

86c: 79%^c

Entry Ar₂B(OBu)₂MgBr (conditions [T, t])

Electrophile Product, Yield^a

4

F₃C CF₃ B(OBu)₂MgBr

2

84b

Br OH

OMe CHO

85d

F₃C

CF₃

CHO

OH OMe

86d: 83%^c

5

B(OBu)₂MgBr

OMe 2

84c (25 °C, 1 h)

I

CO₂Et

85a

CO2Et

MeO

86e: 96%^d

6 84c

NH₂

I Cl

CO₂Et

85e ^MeO

CO2Et

NH₂ Cl

86f: 93%^d

7 84c ^Br

N H

tBu O

85f ^MeO

N H

tBu O

86g: 79%^e

8

B(OBu)₂MgBr 2

84d (0 °C, 30 min)

Br

CO2Et

85g

CO₂Et

86h: 95%^e

9

B(OBu)₂MgBr

CO₂Et 2

84e (25 °C, 1 h)

Br

OMe

85h

EtO2C

OMe

86i: 83%^c

10

B(OBu)2MgBr

CN 2

84f (25 °C, 1 h)

Br

Me O

85i

NC

Me O

86j: 82%^c

11

B(OBu)2MgBr

SMe 2

84g (25 °C, 1 h)

N H Br

85j ^NH

MeS

86k: 92%^e

Entry Ar₂B(OBu)₂MgBr (conditions [T, t])

Electrophile Product, Yield^a

12

B(OBu)₂MgBr

SMe 2

5g

Br OH

OMe CHO

85d

CHO

OH OMe MeS

86l: 87%^e

[a] Yield of isolated, analytically pure product as determined by 1H NMR. [b] Obtained after Pd-catalyzed cross-coupling (Pd(PPh3)4 (4 mol%), Cs2CO3 (1 equiv), THF/EtOH (1:1), 65 °C, 2 h). [c]

Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2CO3 (2 equiv), THF/EtOH (1:1), DMF, 65 °C, 12 h). [d] Obtained after Pd-catalyzed cross-coupling (PdCl2 (4 mol%), K3PO4

(2 equiv), THF/EtOH (1:1), 65 °C, 2 h). [e] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2CO3 (2 equiv), THF/EtOH (1:1), 65 °C, 6 h). dppf = 1,1´-bis(diphenylphosphino)ferrocene.

Remarkably, functionalized heteroaryl bromides as well as chlorides (79h-k) or benzyl chlorides (79l and 79m) readily afford the corresponding diheteroaryl- or dibenzylborates using the direct Mg-insertion in the presence of B(OBu)3 and LiCl. Subsequent cross-coupling reactions with substituted aryl halides (chlorides, bromides, iodides; 85b, 85g, 85kn) furnished the expected polyfunctional aromatics and heteroaromatics 86m-s in 8093% yield (Scheme 47).

Scheme 47. Preparation of heterocyclic organoborates of type 84 followed by Suzuki-type cross-coupling reactions with aryl halides (FG = functional group).

Thus, treatment of ethyl 5-bromofuroate (79h) furnished the functionalized difurylborate 84h (25 °C, 1 h) leading after a Pd-catalyzed cross-coupling with 4-bromobenzonitrile (85k) to the disubstituted furan 86m in 80% yield (Table 10, entry 1). Furthermore, 3-bromothiophene (79i) or 2-chlorothiophene (79j) provided after borylation (Mg (1.6 equiv), LiCl (1.1 equiv), B(OBu)3 (0.5 equiv), 25 °C, 30 min) the corresponding thiophenylborates 84i and 84j.

Suzuki-type cross-couplings of 84ij with substituted 3-iodo- or 3-chloropyridines (85lm) the functionalized pyridines 86no in 8693% yield (Table 10, entries 2 and 3). Similarly, 3-bromobenzo[b]furan (79k) reacted with Mg/LiCl/B(OBu)3 (1.6 equiv/ 1.1 equiv/ 0.5 equiv) via direct Mg-insertion (25 °C, 30 min) producing the corresponding heteroarylborate 84k.

Subsequent Pd-catalyzed cross-coupling reaction with methyl 4-bromoanthranilate (85n)

afforded functionalized benzofuran 86p in 84% yield (Table 10, entry 4). In contrast, the direct magnesium insertion into benzylic carbon-halogen bonds predominantly generates dimers, via the Wurtz-Fittig pathway.²¹⁰ The outstandingly high reactivity of such benzylmagnesium intermediates serves as explanation. However, the direct magnesium insertion in the presence of borate resolves this synthetic problem. Moreover, in comparison to the alternative direct zinc insertion with benzyl chlorides, higher rates of reaction could be observed with magnesium, taking advantage of the greater oxidation potential. For instance, the direct Mg-insertion (1.6 equiv, LiCl (1.1 equiv), 25 °C, 1 h) in the presence of B(OBu)3

(0.5 equiv) with 4-fluorobenzyl chloride (79l) leading to the benzylborate 84l is approximately 12 times faster than the direct zinc insertion^207,211 in the absence of borate (25 °C, 12 h). Furthermore, the generated benzylborate by in situ trapping is water-stable.

From a practical point of view, subsequent cross-coupling reactions are more convenient.

Remarkably, using the in situ generation of benzylborates, such as 84l, only negligible amounts of dimeric homocoupling product were observed. Thus, the 4-fluorobenzylborate derivative 84l provided after Pd-catalyzed cross-coupling the expected functionalized arene 86q in 88% yield (Table 10, entry 5). Similarly, 3,4,5-trimethoxybenzyl chloride 79m also reacted smoothly with Mg/LiCl/B(OBu)3 (1.6 equiv/ 1.1 equiv/ 0.5 equiv) via direct Mg-insertion (25 °C, 1 h) affording the methoxy-substituted benzylborate 84m. Subsequent Suzuki cross-coupling with aryl halides, such as the iodoaniline 85b and ethyl 4-bromobenzoate (85g), led to the corresponding aniline derivative 86r and the substituted benzoate 86s in 8489% yield (Table 10, entry 6 and 7).

Table 10. Preparation of polyfunctional heteroaryl- or benzylborate derivatives of type 84 via direct magnesium insertion in the presence of LiCl and B(OBu)3 from the corresponding heteroaryl bromides or chlorides as well as benzyl chlorides and subsequent Suzuki-type cross-coupling with organic halides of type 85.

Entry R2B(OBu)2MgBr (conditions [T, t])

Electrophile Product, Yield^a

1

EtO₂C O B(OBu)₂MgBr 2

84h (25 °C, 1 h) ^Br

CN

85k

EtO₂C O

CN

86m: 80%^b

210 R. Fittig, J. König, Justus Liebigs Annal. Chem. 1867, 144, 277.

211 A. Metzger, M. A. Schade, P. Knochel, Org. Lett. 2008, 10, 1107.

Entry R₂B(OBu)₂MgBr (conditions [T, t])

Electrophile Product, Yield^a

2 ^S

B(OBu)2MgBr 2

84i (25 °C, 30 min) ^N

I Cl

85l ^N

S

Cl

86n: 93%^c

3

S B(OBu)₂MgCl 2

84k (25 °C, 30 min)

N

CO₂Me MeO2C

Cl

85m

N

CO₂Me MeO₂C

S

86o: 86%^e

4 ^O

B(OBu)2MgBr 2

84i (25 °C, 30 min)

NH2 CO₂Me

Br

85n

O

MeO₂C NH₂

86p: 84%^e

5

F

B(OBu)₂MgCl 2

84l (25 °C, 1 h)

N I

CO₂Et N N

85o

N

CO₂Et F

N N

86q: 88%^d

6 ^OMe

B(OBu)2MgCl

MeO OMe

2

84m (25 °C, 1 h)

NH₂ I

CN

85b

NH₂

CN MeO

MeO

OMe

86r: 89%^e

7 84m

Br

CO2Et

85g

MeO CO2Et

MeO

OMe

86s: 84%^e

[a] Yield of isolated, analytically pure product as determined by 1H NMR. [b] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2CO3 (2 equiv), THF/EtOH (1:1), DMF, 65 °C, 12 h). [c] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2CO3 (2 equiv), THF/EtOH (1:1), DMF, 65 °C, 1 h). [d] Obtained after Pd-catalyzed cross-coupling (Pd(PPh3)4

(4 mol%), K3PO4 (2 equiv), THF/EtOH (1:1), 65 °C, 2 h). [e] Obtained after Pd-catalyzed cross-coupling (PdCl2(dppf) (4 mol%), Cs2CO3 (2 equiv), THF/EtOH (1:1), 65 °C, 6 h). dppf = 1,1´-bis(diphenylphosphino)ferrocene.

Among organometallic reagents, organoboron compounds have the remarkable ability to undergo oxidation reactions with oxidizing reagents such as H2O2 providing the corresponding alcohols. Thus, 1,3,5-trichlorobenzene (79n) efficiently reacted via magnesium insertion in the presence of borate (Mg (1.6 equiv), LiCl (1.1 equiv), B(OBu)3 (0.5 equiv), 25 °C, 1 h) affording the borate 84n. Oxidation using H2O2 and aq. NaOH (25 °C, 2 h) furnished 3,5-dichlorophenol (87) in 79% yield (Scheme 48).

Scheme 48. Preparation of the diarylborate 84n followed by oxidation leading to the phenol 87.

Remarkably, primary and secondary alkyl bromides such as allyl bromide (79o) or 3-bromocyclohexene (79p) efficiently react with Mg/LiCl/B(OBu)3 affording smoothly the dialkylborates 84o or 84p (Scheme 49). Similar to Mg-insertion reactions with benzyl chlorides or bromides, dimeric homo-coupling products were avoided due to the in situ trapping with B(OBu)3. Subsequent Pd-catalyzed cross-couplings (PdCl2(dppf) (4 mol%, Cs2CO3 (2 equiv), EtOH, THF, 65 °C, 6 h) with the aniline derivative 85e or the benzamide 85f furnished the expected substituted arenes 88a and 88b in 8187% yield (Scheme 49).

Scheme 49. Preparation of allylborates like 84o and 84p leading after Pd-catalyzed cross-coupling to the functionalized arenes of type 88.

Furthermore, the diallylborate 84o prepared from allyl bromide (79o) added smoothly to 4-chlorobenzaldehyde (85p; 25 °C, 1 h) providing the substituted allylalcohol 89a in 90%

yield (Scheme 50). Generally, arylboron compounds only add to aldehydes via transition metal catalysis, preferable using Rh-catalysts.²¹² However, the in situ generated heteroarylborate 84i, which includes stoichiometric amounts of Lewis acidic magnesium salts, provided with benzofuran-2-carbaldehyde (85q), in the absence of transition metals, the corresponding carbinol 89b in 59% yield (Scheme 50).

Scheme 50. Preparation of a secondary alcohols of type 89 using the organoborates 84o or 84i.

Besides magnesium, as mentioned above, various oxidizable metals are feasible in the described method for the in situ preparation of organoborates. Hence, we further explored the use of aluminium in the direct metal insertion in the presence of borates. Remarkably, Knochel et al. recently reported the preparation of aluminium reagents for the first time via direct metal insertion.²¹³ Aluminium metal is inexpensive and the waste products are generally non-toxic as well as non-corrosive. However, merely heavy transition metals or heavy main group elements enable the direct metal insertion of aluminium into carbon-halogen bonds. Nevertheless, we could show that borates such as B(OBu)3 also permit the direct aluminium insertion into carbon-halogen bonds of various aryl bromides like 1-bromo-bis(trifluoromethyl)benzene (79b; 65 °C, 1 h) affording the arylborate 84b. Subsequent Suzuki-type catalyzed cross-coupling (Pd(PPh3)4 (4 mol%), Cs2CO3 (2 equiv), THF, EtOH, 65 °C, 2 h) with ethyl 4-iodobenzoate (85a) produced the polysubstituted biphenyl 86t in 69%

yield (Scheme 51). Similarly, the bromo-terephthalate 79p furnished via direct insertion reaction with aluminium (3 equiv, 65 °C, 7 h) in the presence of B(OBu)3 (0.5 equiv) the functionalized arylborate 84p. Thereafter, the Pd-catalyzed cross-coupling (Pd(PPh3)4 212 K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169.

213 T. Blümke, Y.-H. Chen, Z. Peng, P. Knochel, Nature Chem. 2010, 2, 313.

(4 mol%), Cs2CO3 (2 equiv), THF, EtOH, DMF, 65 °C, 12 h) with 4-bromoanisole (85h;

furnishes the polyfunctional biphenyl 86u in 72% yield (Scheme 51).

Br F₃C

CF₃

B(OBu)₂AlX₂

CF₃

F₃C I

CO2Et

CO₂Et F₃C

CF₃ 84b: >90%

2

Pd(PPh₃)₄(4 mol%), Cs₂CO₃(2 equiv), THF, EtOH, 65 °C, 2 h Al (3 equiv)

LiCl (1.5 equiv), B(OBu)₃(0.5 equiv) 65 °C, 1 h, THF

(85a; 0.8 equiv)

86t: 69%

79b

Br

CO₂Et CO₂Et

B(OBu)₂AlX₂

CO2Et CO₂Et

Br

OMe

OMe

CO₂Et CO2Et

84p: >90%

2

Pd(PPh3)4(4 mol%), Cs₂CO₃(2 equiv), THF, EtOH, DMF, 65 °C, 12 h Al (3 equiv)

LiCl (1.5 equiv), B(OBu)3(0.5 equiv) 65 °C, 7 h, THF

(85h; 0.8 equiv)

86u: 72%

79p

Scheme 51. Preparation of polysubstituted arylborates 84b und 84p via direct aluminium insertion in the presence of B(OBu)3 followed by Pd-catalyzed cross-coupling reactions.

Remarkably, we could clearly demonstrate the accelerating effect of borates in direct aluminium insertion using merely catalytic amounts of borate leading to the corresponding organoaluminium reagents. Thus, B(OBu)3 or BEt3 applied in catalytic amounts (10 mol%) proved to enable the direct aluminium insertion with the activated aryl bromide 79b affording the substituted arylaluminium reagent 90 in ca. 90% yield (Scheme 52). Compared to the reaction times using substoichiometric amounts of borate (B(OBu)3 (0.5 equiv), Scheme 51), the direct aluminium insertion reaction (Al (3 equiv), LiCl (1.5 equiv), BR3 (10 mol%)) proceeded with similar rates (B(OBu)3: 65 °C, 90 min; BEt3: 65 °C, 30 min). Moreover, using the same reaction conditions, no direct aluminium insertion with 79b was observed after 24 h at 65 °C in the absence of borates or LiCl.

Br F₃C

CF3

AlX_n

CF₃ F₃C

90: >90%

Al (3 equiv) LiCl (1.5 equiv), B(R)3(10mol%)

65 °C, THF

B(OBu)₃ 10 mol% 65 °C, 90 min B(Et)3 10 mol% 65 °C, 30 min 79b

Scheme 52. Preparation of substituted aluminium reagent 90 via the direct metal insertion, catalyzed by B(OBu)3

(10 mol%) or BEt3 (10 mol%).

In summary, we have demonstrated an efficient and low-cost one-step synthesis of polyfunctional borates via accelerated direct metal insertion tolerating a wide range of functional groups. The method proved to be highly flexible and fast by means of the

accelerating effect of B(OBu)3 and LiCl during the direct metal insertion allowing the conversion of functionalized primary and secondary alkyl, alkenyl, benzyl or aryl as well as heteroaryl bromides into the corresponding organoborates. Furthermore, we demonstrated the practicability of the prepared organoborates bearing sensitive functional groups in the uncatalyzed addition to aldehydes and in Suzuki-type cross-couplings. In addition, the substantial accelerating effect of B(OBu)3 has been demonstrated in the direct metal insertion with aryl bromides using less reactive metals, such as Al, Ca, and Zn. Moreover, we could show that Li, K and Na are also feasible for the in situ preparation of organoborates via direct metal insertion.

3.

Functionalization of Pyridines and Related Heterocycles

Im Dokument Synthesis, functionalization and polymerization of heterocycles using frustrated Lewis Pairs, Boron, Magnesium and Zinc reagents (Seite 75-88)